Process of preparing 3-fluoro-5(((1r,2ar)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1h-cyclopenta[cd]inden-7-yl)-oxy)benzonitrile

ABSTRACT

Disclosed herein are processes for preparing certain intermediates useful in the synthesis of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. Nonprovisional Application claims the benefitof PCT International Application No. PCT/CN2020/121780, filed on Oct.19, 2020, the entire contents of which are hereby incorporated byreference in their entirety.

FIELD OF THE DISCLOSURE

Disclosed herein are processes for preparing certain intermediatesuseful in the synthesis of3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(hereinafter Compound (I)) having the structure:

or a pharmaceutically acceptable salt thereof.

BACKGROUND

Compound (I) is a hypoxia inducible factor-2α (HIF-2α) inhibitor and isbeing developed for treating diseases mediated by aberrant activity ofHIF-2α including cancer, such as renal cancer, glioblastoma,neuroblastoma, pheochromocytomas and paragangliomas, somatostatinomas,hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitarytumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumorsand non-cancer diseases such as pulmonary artery hypertension (PAH),reflux esophagitis, hepatic steatosis, NASH, inflammatory disease suchas inflammatory bowel disease, autoimmune disease such asGraft-versus-Host-Disease, and iron overload.

Synthesis of Compound (I) is disclosed in Example 5 of PCT ApplicationNo. Publication No. WO 2020/214853, filed on Apr. 16, 2020. There is aneed for alternative processes that allow for large scale synthesis ofCompound (I) in a cost-effective manner. The processes disclosed hereinfullfill this and related needs.

SUMMARY

Provided herein is a process for preparing3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile(hereinafter compound 11) having the structure:

that makes it feasible to produce Compound (I) in high purity, includingenantiomeric purity, and yield in a cost-effective manner and that issuitable for use in the preparation of Compound (I) on a commercialscale. Also, provided are processes for preparing certain intermediatesused in such process.

In one aspect, provided is a process of preparing compound (11):

comprising reducing the keto moiety of compound (10):

with a suitable reducing agent in a suitable organic solvent; andoptionally in the presence of an organic acid.

In a second aspect, provided is a process of preparing compound (10):

comprising reacting compound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent.

In a third aspect, the process of the first aspect, further comprisingpreparing compound (10):

by reacting compound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent.

In a fourth aspect, provided is a process for preparing compound (9):

comprising carrying out oxidative cleavage of the vinylidene moiety ofcompound (8):

with a suitable oxidizing agent in a suitable organic or aqueous organicsolvent.

In a fifth aspect, the processes of the second and third aspects,further comprise preparing compound (9):

by carrying out oxidative cleavage of the vinylidene moiety of compound(8):

with a suitable oxidizing agent in a suitable organic or aqueous organicsolvent.

In a sixth aspect, provided is a process for preparing compound (8):

comprising performing intramolecular cyclization between the alkene andbromo groups in compound (7):

by treating compound (7) with a palladium catalyst in the presence of abase in a suitable organic or aqueous organic solvent.

In a seventh aspect, the processes of the fourth and fifth aspects,further comprise preparing compound (8):

by performing intramolecular cyclization between the alkene and bromogroups in compound (7):

with a palladium catalyst in the presence of a base in a suitableorganic or aqueous organic solvent.

In an eighth aspect, provided is a process for preparing compound (7):

comprising brominating compound (6):

with a brominating agent in the presence of a deprotonating agent in asuitable organic solvent.

In a ninth aspect, the processes of the sixth and seventh aspects,further comprise preparing compound (7):

by treating compound (6):

with a brominating agent in the presence of a deprotonating agent in asuitable organic solvent.

In a tenth aspect, the processes of the eighth and ninth aspects,further comprise preparing compound (6):

by treating compound (5):

with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane in thepresence of(S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamideand a base in a suitable organic solvent.

In an eleventh aspect, the process of tenth aspect, further comprisespreparing compound (5):

by treating compound (4):

with an organolithium reagent in a suitable organic solvent.

In a twelfth aspect, the process of eleventh aspect, further comprisespreparing compound (4):

by treating compound (3):

with a fluorinating agent in a suitable organic solvent.

In a thirteenth aspect, the process of twelfth aspect, further comprisespreparing compound (3):

by treating compound (2):

with an oxidizing agent in a suitable organic solvent.

In a fourteenth aspect, the process of thirteenth aspect, furthercomprises preparing compound (2):

by treating compound (1):

with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal,trimethylsilyl chloride, and 1,2-dibromoethane in a suitable organicsolvent.

DETAILED DESCRIPTION Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

As used herein, the term “reacting” or “treating” when describing acertain process is used as known in the art and generally refers to thebringing together of chemical reagents in such a manner so as to allowtheir interaction at the molecular level to achieve a chemical orphysical transformation. The reacting steps of the processes describedherein can be conducted for a time and under conditions suitable forpreparing the identified product.

“Suitable organic solvent” refers to an organic solvent which, under thereaction conditions of the processes disclosed herein, does not enterinto any appreciable reaction with either the reactants, intermediatesan/or the products at the temperatures at which the reactions arecarried out. A given reaction disclosed herein can be carried out in oneorganic solvent or a mixture of two or more organic solvents. Examplesof suitable organic solvents that can be used in the reactions describedherein include: halogenated solvents such as carbon tetrachloride,chloroform, dichloromethane, and the like; ethers such astetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane,diethyl ether, methyl t-butyl ether, and the like; alcohols such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, n-butylalcohol, tert-butyl alcohol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol,and the like; hydrocarbons such as benzene, toluene, xylene,cyclohexane, pentane, hexane, heptane, and the like. Additional organicsolvents that can be used in the reactions described herein includepolar organic solvents including, but not limited to, acetonitrile,dimethylformamide, ethyl acetate, alcohols, and the like. Examples ofsuitable organic solvents that can be used in the reactions describedherein include: halogenated solvents such as carbon tetrachloride,chloroform, dichloromethane, 1,2-dichloroethane, and the like; etherssuch as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane,1,4-dioxane, diethyl ether, methyl t-butyl ether, and the like; alcoholssuch as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,n-butyl alcohol, tert-butyl alcohol, 1-, 2-, or 3-pentanol, neo-pentylalcohol, and the like; aromatic hydrocarbons such as benzene, toluene,xylene, and the like; alkanes such as cyclohexane, cyclopentane,pentane(s), hexane(s) (including n-hexane), heptane(s) (includingn-heptane), isooctane(s) and the like. Additional organic solvents thatcan be used in the reactions described herein include polar organicsolvents including, but not limited to, acetonitrile, dimethylformamide,ethyl acetate, alcohols, and the like. When polar organic solvents(e,g., alcohols, acetonitrile, DMF) contain water they are referred toherein as aqueous organic solvent. Depending on the reaction step,solvents that are suitable for the particular reaction step can bereadily selected by a person skilled in the art.

For example, in the preparation of compound (2), besides, THF, thereaction was also carried out in MTBE, 2-methylTHF, or toluene solvent.In the preparation of compound (3), the reaction was also carried out inTHF solvent. In the preparation of compound (4), the reaction was alsocarried out in CHC1₃ solvent. In the preparation of compound (5), thereaction was also carried out in 2-methyl THF, n-heptane, or MTBEsolvent. In the preparation of compound (8), the reaction was alsocarried out in DMF, 1,4-dioxane, THF, 2-methyl THF, toluene, oracetonitrile solvent. In the preparation of compound (9), the reactionwas also carried out in a mixture of DCM/ACN/water. In the preparationof compound (10), the reaction was also carried out in DMF, ACN,2-methyl THF, or toluene solvent. In the preparation of compound (11),the reaction was also carried out in THF, CH3OH, TFA/THF, or HOAc/THFsolvent.

In addition, the reactions were carried out at various temperatures.Reaction temperatures that were used in the preparation of compound (2)included 20° C., 40° C., 60° C., and refluxing. Reaction temperaturesthat were used in the preparation of compound (3) included 0-15° C. and15-25° C. Reaction temperatures that were used in the preparation ofcompound (4) included 0-10° C., 10-20° C., 20-30° C., and 30-40° C.Reaction temperatures that were used in the preparation of compound (5)included −30 to −40° C., −40 to −50° C., −50 to −60° C., and −60 to −70°C. Reaction temperatures that were used in the preparation of compound(6) included 35° C., 45 ° C., and 60° C. Reaction temperatures that wereused in the preparation of compound (7) included −100 to −80° C., −80 to−60° C., and −60 to −40° C. Reaction temperatures that were used in thepreparation of compound (8) included 60° C., 70° C. and refluxing.Reaction temperatures that were used in the preparation of compound (10)included 20 to 30° C., and 40° C. Reaction temperatures that were usedin the preparation of compound (11) included 10 to 20° C. and −5 to 5°C.

In addition, the brominating agents that can be used in the preparationof compound (7) herein include bromotrichloromethane,1,2-dibromo-1,1,2,2-tetrachloroethane,1,2-dibromo-1,1,2,2-tetrafluoroethane, carbon tetrabromide,N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin,N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuricacid, monosodium bromoisocyanurate, bromodimethylsulfonium bromide,5,5-dibromomeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone,bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate; and bromineand its equivalents, such as bromine-1,4-dioxane complex,tetrabutylammonium tribromide, trimethylphenylammonium tribromide,benzyltrimethylammonium tribromide, and 1-butyl-3-methylimidazoliumtribromide.

Additionally, bases that were used in the preparation of compound (8)included NaOAc, KOAc, and K₂CO₃;

brominating reagents that were used in the preparation of compound (7)included CBr₄ and CF₂BrCF₂Br;

catalysts that were used in the preparation of compound (8) includedPd(dppf)Cl₂, Pd₂(dba)₃/XPhos, Pd(OAc)₂/PPh₃, and Pd(PPh₃)Cl₂;

fluorinating reagents that were used in the preparation of compound (4)included DAST, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, andHF/SF₄;

oxidizing agents that were used in the oxidation of compound (2) to (3)included 2-iodoxybenzoic acid (MX), RuCl₃/NaBrO₃; TEMPO/NaClO, MnO₂, andTPAP/NMO.

oxidizing agents that were used in the oxidation of compound (8) to (9)included RuCl₃/NaIO₄, RuCl₃/Oxone® and O₃; and

reducing agents that were used in the reduction of compound (10) to (11)included LiBH₄ and NaBH₄.

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy,spectrophotometry, or mass spectrometry; or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography. The compounds obtained by the reactions can be purifiedby any suitable method known in the art. For example, chromatography(medium pressure) on a suitable adsorbent (e.g., silica gel, alumina andthe like), HPLC, or preparative thin layer chromatography; distillation;sublimation, trituration, or recrystallization. The purity of thecompounds, in general, are determined by physical methods such asmeasuring the melting point (in case of a solid), obtaining an NMRspectrum, or performing a HPLC separation.

“Cyclic ether” refers to tetrahydrofuran, 2-methyltetrahydrofuran, or1,4-dioxane.

“Alcohol” refers to an aliphatic hydrocarbon compound that carries ahydroxy group. Representative examples include, but are not limited to,methanol, ethanol, propanol, butanol, and the like.

“About” as used herein means±10%, preferably±5% of listed value. Forexample, a reaction carried out at about 10° C. includes 9° C., 11° C.,and all temperatures contained in between 9° C. and 11° C.

“A” and “an” as used herein means one or more (in some embodiments, 1,2, or 3), unless context clearly dictates otherwise. For example, “asuitable organic solvent” or “an organic solvent” includes a singlesolvent and includes mixture of solvents, unless context clearlydictates otherwise; in the case that a single specific solvent isrecited in an embodiment, then “a” and “an” means one.

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy,spectrophotometry, or mass spectrometry; or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography. The compounds obtained by the reactions can be purifiedby any suitable method known in the art. For example, chromatography(medium pressure) on a suitable adsorbent (e.g., silica gel, alumina andthe like), HPLC, or preparative thin layer chromatography; distillation;sublimation, trituration, or recrystallization. The purity of thecompounds, in general, are determined by physical methods such asmeasuring the melting point (in case of a solid), obtaining an NMRspectrum, or performing a HPLC separation.

Embodiments

1A. In embodiment 1A, the process of preparing compound (11):

is as described in the first aspect of the Summary.

1B. In embodiment 1B, the process of embodiment 1A is wherein thereducing agent is sodium borohydride, lithium borohydride, sodiumacetoxy borohydride, or sodium cyanoborohydride.

1. In embodiment 1, the process of preparing compound (11):

according to embodiment 1A comprises reducing the keto moiety ofcompound (10):

with:

(a) sodium borohydride in an organic solvent selected from the groupconsisting of (i) an alcohol containing acetic acid or trifluoroaceticacid, (ii) a cyclic ether, and (iii) a mixture of a cyclic ether and analcohol; wherein the cyclic ether of (ii) and the mixture of a cyclicether and an alcohol of (iii) optionally contain acetic acid ortrifluoroacetic acid; or

(b) lithium borohydride in a suitable organic solvent optionallycontaining acetic acid or trifluoroacetic acid.

2. In embodiment 2, the process of embodiment 1A, 1B, or 1 is whereinthe reduction of the keto group of compound (10) is carried out withsodium borohydride in tetrahydrofuran, 2-methyltetrahydrofuran, amixture of tetrahydrofuran or 2-methyltetrahydrofuran and methanol,tetrahydrofuran containing acetic acid or trifluoroacetic acid,2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid,or methanol containing acetic acid or trifluoroacetic acid.

3. In embodiment 3, the process of embodiment 2 is wherein the organicsolvent is a mixture of tetrahydrofuran and methanol and the reaction iscarried out at about -5° C. to about 30° C.

4. In embodiment 4, the process of embodiment 2 is wherein the organicsolvent is a mixture of tetrahydrofuran and methanol and the reaction iscarried out at about −5° C. to about 5° C.

5A. In embodiment 5A, the process of preparing compound (10):

is as described in the second aspect in the Summary.

5. In embodiment 5, the process of embodiment 5A comprises reactingcompound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent other than dimethylformamide.

6. In embodiment 6, the process of any one of embodiments 1A to 4,further comprising preparing compound (10):

by reacting compound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent.

7. In embodiment 7, the process of embodiment 5A, 5 or 6 is wherein thebase is an inorganic base.

8. In embodiment 8, the process of embodiment 7 is wherein the inorganicbase is cesium carbonate or potassium carbonate

9. In embodiment 9, the process of any one of embodiments 5A and 6 to 8is wherein the organic solvent is tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide, acetonitrile, or toluene.

10. In embodiment 10, the process of embodiment 9 is wherein the organicsolvent is tetrahydrofuran.

11. In embodiment 11, the process of any one of embodiments 5A to 10 iswherein the reaction is carried out at about 20° C. to about 40° C.

12. In embodiment 12, the process of any one of embodiments 5A to 11,further comprising crystallizing compound (10) from a mixture of anether and an alkane solvent.

13. In embodiment 13, the process of embodiment 12 is wherein compound(10) is crystallized from a mixture of methyl tert-butyl ether andn-heptane.

14A. In embodiment 14A, provided is a process for preparing compound(9):

as described in the fourth embodiment of the Summary.

14. In embodiment 14, the process of embodiment 14A comprises carryingout oxidative cleavage of the vinylidene moiety of compound (8):

with (i) sodium periodate in the presence of ruthenium chloride inaqueous acetonitrile, (ii) Oxone in the presence of ruthenium chloridein a suitable organic or aqueous organic solvent, or (iii) Ozone in asuitable organic or aqueous organic solvent.

15. In embodiment 15, the process of any one of embodiments 5A to 13,further comprising preparing compound (9):

by carrying out oxidative cleavage of the vinylidene moiety of compound(8):

with a suitable oxidizing agent agent in a suitable organic or aqueousorganic solvent.

16. In embodiment 16, the process of embodiment 15 is wherein theoxidative cleavage of the vinylidene is carried out with (i) sodiumperiodate or Oxone in the presence of ruthenium chloride or (ii) Ozone.

17. In embodiment 17, the process of any one of embodiments 14A to 16 iswherein the solvent is a mixture of dichloromethane, acetonitrile, andwater or the solvent is aqueous acetonitrile.

18. In embodiment 18, the process of any one of embodiments 14A to 17 iswherein the oxidative cleavage of the vinylidene is carried out withsodium periodate in the presence of catalytic amount of rutheniumchloride in aqueous acetonitrile.

19. In embodiment 19, the process of any one of embodiments 14A to 18,further comprising purification of compound (9) from a mixture of anether and an alkane solvent.

20. In embodiment 20, the process of embodiment 19 is whereinpurification of compound (9) is from a mixture of methyl tert-butylether and n-heptane.

21A. In embodiment 21A, provided is a process for preparing compound(8):

is as defined in the sixth aspect of the Summary.

21. In embodiment 21, the process of embodiment 21A comprises performingintramolecular cyclization between the alkene and bromo groups incompound (7):

by treating compound (7) with a palladium catalyst in the presence of abase in a suitable organic solvent other than dimethylformamide.

22. In embodiment 22, the process of any one of embodiments 14A to 20,further comprising preparing compound (8):

by performing intramolecular cyclization between the alkene and bromogroups in compound (7):

with a palladium catalyst in the presence of a base in a suitableorganic solvent.

23. In embodiment 23, the process of embodiment 21A, 21 or 22 is whereinthe palladium catalyst is Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂,Pd(PPh₃)₂(OAc)₂, Pd₂(dba)₃/XPhos, orPd(1,2-bis(diphenylphosphino)ethane)(OAc)₂, and the organic solvent isacetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene,1,4-dioxane, or dimethylformamide.

24. In embodiment 24, the process of embodiment 23 is wherein the baseis sodium acetate, potassium acetate, sodium carbonate, potassiumcarbonate, or cesium carbonate.

25. In embodiment 25, the process of any one of embodiments 21A, 21, 22,or 24 is wherein the palladium catalyst is Pd(PPh₃)₂Cl₂, the base ispotassium acetate, and the solvent is acetonitrile.

26. In embodiment 26, the process of embodiment 25 is wherein thereaction is carried out between about 60° C. to about 80° C.

27A. In embodiment 27A, provided is a process for preparing compound(7):

is as described in the eighth aspect of the Summary.

27. In embodiment 27, the process of embodiment 27A comprisesbrominating compound (6):

with 1,2-dibromo-1,1,2,2-tetrafluoroethane in the presence of adeprotonating agent in a suitable organic solvent.

28. In embodiment 28, the process of any one of embodiments 21A to 26,further comprising preparing compound (7):

by treating compound (6):

with a brominating agent in the presence of a deprotonating agent in asuitable organic solvent.

29. In embodiment 29, the process of embodiment 28 is wherein thebrominating agent is carbon tetrabromide or1,2-dibromo-1,1,2,2-tetrafluoroethane.

30. In embodiment 30, the process of embodiment 27A, 27 or 28 is whereinthe brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, thedeprotonating agent is lithium diisopropylamide and the solvent istetrahydrofuran.

31. In embodiment 31, the process of embodiment 30 is wherein thereaction is carried at out at about −100° C. to about −20° C.

32. In embodiment 32, the process of any one of embodiments 27A, 27 and28 to 31, further comprising preparing compound (6):

by treating compound (5):

with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane in thepresence of(S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamideand a base in a suitable organic solvent.

33. In embodiment 33, the process of embodiment 32 is wherein the baseis sodium tert-butoxide and the organic solvent is a mixture of methanoland toluene.

34. In embodiment 34, the process of claim 32 or 33, further comprisingpreparing compound (5):

by treating compound (4):

with an organolithium reagent in a suitable organic solvent.

35. In embodiment 35, the process of claim 34 is wherein theorganolithium reagent is n-butyllithium, and the organic solvent istetrahydrofuran, 2-methyltetrahydrofuran, n-heptane and methyltert-butylether.

36. In embodiment 36, the process of embodiment 34 or 35 is wherein thesolvent is tetrahydrofuran.

37. In embodiment 37, the process of any one of embodiments 34 to 36,further comprising preparing compound (4):

by treating compound (3):

with a fluorinating agent in a suitable organic solvent.

38. In embodiment 38, the process of claim 37 is wherein thefluorinating agent is diethylaminosulfur trifluoride,4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, or sulfurtetrafluoride and hydrofluoric acid.

39. In embodiment 39, the process of embodiment 38 is wherein thefluorinating agent is sulfur tetrafluoride and hydrofluoric acid and thesolvent is dichloromethane.

40. In embodiment 40, the process of any one of embodiments 37 to 39,further comprising preparing compound (3):

by treating compound (2):

with an oxidizing agent in a suitable organic solvent.

41. In embodiment 41, the process of embodiment 40 is wherein theoxidizing agent is dimethyl sulfoxide/oxalyl chloride, 2-iodoxybenzoicacid, RuCl₃/NaBrO₃, MnO₂, NaBrO₃/NaHSO₃, or TPAP/NMO.

42. In embodiment 42, the process of embodiment 41 is wherein theoxidizing agent is is TPAP/NMO and reaction is carried indichloromethane, acetonitrile or tetrahydrofuran, preferablydichloromethane.

42A. In embodiment 42A, the process of embodiment 41 is wherein theoxidizing agent is RuCl₃/NaBrO₃,

43. In embodiment 43, the process of any one of embodiments 40 to 42A,further comprising preparing compound (2):

by treating compound (1):

with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal,trimethylsilyl chloride, and 1,2-dibromoethane in a suitable organicsolvent.

44. In embodiment 44, the process of embodiment 43, is wherein theorganic solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

EXAMPLES Abbreviations:

-   ACN: acetonitrile-   AcOH or HOAc: acetic acid-   AlkylFluor: CAS Registry No. 2043361-32-4-   Cs₂CO₃: cesium carbonate-   DAST: diethylaminosulfur trifluoride-   DCM: dichloromethane-   HF: hydrofluoric acid-   HCl: hydrochloric acid-   KOAc: potassium acetate-   LDA: lithium diisopropylamide-   MTBE: methyl tert-butyl ether-   NMO: N-Methylmorpholine N-oxide-   MeOH: methanol-   NaBH₄: sodium borohydride-   NaIO₄: sodium perodiate-   n-BuLi: n-butyllithium-   Pd(PPh₃)₂(OAc)₂: bis(acetato)bis(triphenylphosphine)palladium(II)-   Pd(PPh₃)₂Cl₂: bis(triphenylphosphine)palladium(II) dichloride-   Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)-   PyFluor: 2-pyridinesulfonyl fluoride-   RuCl₃·3H₂O: ruthenium (III) chloride hydrate-   SF₄: sulfur tetrafluoride-   SulfoxFluor:    [methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl}-λ⁶-sulfanylidene]cyanamide-   TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or    (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-   TFA: trifluoroacetic acid-   THF: tetrahydronfuran-   TPAP: tetrapropylammonium perruthenate-   t-BuONa: sodium tert-butoxide-   XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 1 Synthesis of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

Step 1: ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate

To a mixture of zinc (211.36 g, 3.23 mol, 1.31 eq.) in THF (1.50 L) wasadded 1,2-dibromoethane (13.88 g, 73.89 mmol, 0.030 eq.) and TMSCl(53.52 g, 492.59 mmol, 0.20 eq.) in one portion. The mixture was stirredat 25° C. for 0.5 h, then a solution of 2-bromo fluoro-benzaldehyde (500g, 2.46 mol, 1.00 eq.) and ethyl 2-bromo-2,2-difluoro-acetate (549.93 g,2.71 mol, 1.10 eq.) in THF (1.50 L) was added to the mixture dropwiseover 1 h under refluxing, and the reaction mixture was stirredcontinually under refluxing for 1 h. The reaction mixture was cooled,then filtered, and the cake was washed with ethyl acetate. The filtratewas quenched with 1.0 M aqueous HCl (800 mL), then adjusted to pH=5-6and the mixture was extracted with ethyl acetate. The combined organicphase was washed with 10% brine, dried with Na₂SO₄, concentrated invacuum to give the title compound (857.0 g, 88.8% assay purity, 94.5%assay yield) as a yellow oil, which was used for next step withoutfurther purification.

Step 2: ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate

A mixture of NMO (297.86 g, 2.54 mol, 1.40 eq.), TPAP (15.96 g, 45.41mmol, 0.025 eq.) and 4 Å MS (94.0 g) in DCM (1000 mL) was degassed andpurged with N₂ and a solution of ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (669.00 g,1.82 mol, 88.8% assay, 1.00 eq.) in DCM (1000 mL) was added dropwise at0-5° C. over 1.5 h. The resulting mixture was further stirred at 25° C.for 2 h under N₂ atmosphere, then was filtered through silica gel padand the pad cake was washed with MTBE. The combined filtrate was washedwith 1.0 M aqueous HCl. The combined aqueous phase was extracted withMTBE. The combined MTBE organic phase was washed with H₂O, filteredthrough a silica gel pad and the pad cake was washed with MTBE. Thecombined filtrate was concentrated to give the title compound (561.0 g,95.1% yield) as a yellow oil, which was used for next step withoutfurther purification.

Alternative Method:

To a stirred mixture of ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxy-propanoate (285.9 g,after assay adjustment, 0.874 mol, 1.00 eq.) in acetonitrile (900 mL)and water (900 mL) were added NaH₂PO₄ (63.0 g, 0.525 mol, 0.60 eq.) andRuCl₃ (1.81 g, 8.726 mmol, 0.010 eq.) sequentially at 20-30° C. NaBrO₃(158.27 g, 1.049 mol, 1.20 eq.) was then added in portions at 20-30° C.After further stirring at 20-30° C. for 2 h, the reaction mixture wasdiluted with EtOAc, followed by washing with water, aqueous Na₂SO₃,water and then brine. The organic layer was concentrated to obtain thetitle compound (272.8 g, 95.2% purity, 91.4% yield) as a yellow oil,which was used for next step without further purification.

Step 3: ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate

To an autoclave was charged ethyl3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate (550.00 g, 1.69mol, 1.00 eq.) and DCM (55.5 mL). The mixture was cooled to −78° C. andHF (33.85 g, 1.69 mol, 1.00 eq.) was charged, followed by SF₄ (202.00 g,1.87 mol, 1.11 eq.). The reaction mixture was warmed to room temperatureand stirred at this temperature for 16 h. The reaction mixture wasquenched by adding slowly into saturated aqueous Na₂CO₃ (2.5 L), andthen extracted with petroleum ether. The combined organic layer waswashed with 10% brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was further purified by vacuum distillation to afford the titlecompound (474.0 g, 81.1% yield) as yellow oil.

Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

A stirred solution of ethyl3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate (100.0. g,288.11 mol, 1.00 eq.) in THF (1.0 L) was cooled to −65° C., and n-BuLi(2.5 M, 138.0 mL, 345.0 mol, 1.20 eq.) was added dropwise at −60 to −70°C. over 1 h under nitrogen atmosphere. The resulting mixture was stirredfurther at −65° C. for 1 h, then was quenched with saturated aqueousNH₄Cl at −30 to −40° C., followed by dilution with ethyl acetate andH₂O. After phase separation, the aqueous phase was extracted with ethylacetate and the combined organic layer was washed with 10% brine, driedover Na₂SO₄, filtered and concentrated to give a residue. The residuewas purified by vacuum distillation, and the distillate was trituratedwith petroleum ether at low temperature to give the title compound (41.0g, 64.1% yield) as a white solid.

Example 2 Synthesis of(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

Step 1: (R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a dry 3-neck flask were added2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94.57 g, 562.78 mmol,1.21 eq.),(S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethyl-butanamide(36.51 g, 119.14 mmol, 0.26 eq.), t-BuONa (4.33 g, 45.06 mmol, 0.097eq.), toluene (900 mL) and MeOH (28.8 g, 898.88 mmol, 1.94 eq.). Themixture was stirred at 20° C. under nitrogen atmosphere until a clearsolution formed. The reaction mixture was heated to 60° C., and asolution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (103.09 g,464.14 mmol, 1.00 eq.) in toluene (100 mL) was added slowly over 2 h at60° C. The resulting mixture was stirred continually for 16 h at 60° C.,then cooled to room temperature, quenched with water, and extracted withMTBE. The organic layer was cooled to 0° C. and washed with 1.0 Maqueous HCl, 0.5 M aqueous NaOH, water and 10% brine. The organic layerwas concentrated to give the title compound (146.71g, 73.5% assaypurity, 87.9% assay yield, 90.7% e.e.).

Step 2:(R)-1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

To a dry 3-neck flask were added THF (500 mL) and LDA (356.82g, 25%,832.76 mmol, 2.21 eq.) and then the solution was cooled to −50° C. undernitrogen atmosphere. A solution of(R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (100.00 g,378.50 mmol, 1.00 eq.) in THF (200 mL) was added slowly at −50° C. Theresulting mixture was stirred at −50° C. for 1 h, then cooled to −80° C.to form solution A.

To another dry 3-neck flask were added 1,2-dibromotetrafluoroethane(196.66 g, 756.91 mmol, 2.00 eq.) and THF (100 mL), and the solution wascooled to −80° C. Solution A was slowly added with stirring and whilemaintaining the reaction temperature at about −80° C. The mixture wasstirred at −80° C. for additional 30 min and then slowly quenched byslowly adding a solution of AcOH (75.00 g, 1248.96 mmol, 3.30 eq.) inTHF (75 mL) at temperature below −60° C. The mixture was warmed slowlyto room temperature and diluted with water. The mixture was extractedwith MTBE, and the combined organic layer was washed with water and 10%brine. The organic layer was concentrated to give the title compound asa solution in THF (204.40g, 50.4% assay purity, 79.3% assay yield).

Step 3:(R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol

Into a solution of(R)-1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol(100.00 g, 291.47 mmol, 1.00 eq.) in acetonitrile (1.50 L) were addedKOAc (86.50g, 881.39 mmol, 3.03 eq.) and Pd(PPh₃)₂Cl₂ (10.30 g, 14.67mmol, 0.050 eq.) under N₂ atmosphere. The mixture was stirred for 4 h at80° C. and then concentrated under vacuum to about 1/3 volume. Theresidue was diluted with MTBE and washed with water. The organic layerwas diluted with n-heptane and passed through a silica gel pad (200 g).The pad was rinsed with MTBE/n-heptane=1/3 to wash out the product. Theeluent was concentrated and exchange the solvent into acetonitrile togive the title compound as a solution in acetonitrile (120.15 g, 51.7%assay purity, 81.3% assay yield, 90.6% e.e.).

Step 4:(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

To a stirred mixture of(R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol(80.00 g, 305.13 mmol, 1.00 eq.) in ACN (1200 mL) and H₂O (3200 mL) wasadded RuCl₃·3H₂O (4.00 g, 15.30 mmol, 0.050 eq.), followed by NaIO₄(456.87 g, 2.14 mol, 7.01 eq.) in portions while maintaining thereaction temperature at 10 to 20° C. After stirring further at 10 to 20°C. for 1 h, MTBE (800 mL) was added to the mixture and the mixture wasfiltered through a Celite layer. The Celite solid cake was washed withMTBE. The organic layer was separated from the combined filtrate, andthe aqueous layer was extracted with MTBE. The combined organic layerwas washed with 5% aqueous Na₂SO₃ and 10% aqueous Na₂SO₄. The organiclayer was concentrated, and the residue was dissolved in MTBE andn-heptane. The solution was filtered through a silica gel pad (200 g)and the pad solid cake was rinsed with MTBE/n-heptane=1/3. The combinedeluent was concentrated to about 3V to precipitate out the product whichwas filtered and dried to give the title compound as a white solid(70.62 g, 88.4% assay, 77.5% assay yield, 91.7% e.e.).

Example 3 Synthesis of3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

Step 1:(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred mixture of(R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one (100.00 g, after assay adjustment, 378.57 mmol, 1.00 eq., 91.7%e.e.) in THF (500 mL) were added 3-fluoro-5-hydroxybenzonitrile (57.10g, 416.45 mmol, 1.10 eq.) and Cs₂CO₃ (74.01 g, 227.15 mmol, 0.60 eq.) atroom temperature. The resulting mixture was stirred at 40° C. for 20 h.The mixture was cooled to room temperature and MTBE was added, followedby water. After layer separation, the aqueous layer was extracted withMTBE and the combined organic layer was washed with 5% aqueous Na₂CO₃and then 10% brine. The organic layer was concentrated and the residuewas recrystallized from MTBE/n-heptane=3/20 to give the title compoundas a yellow solid (145.78 g, 84.4% assay purity, 85.2% assay yield,98.4% e.e.).

Step 2:3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile

To a stirred solution of(R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile(50.00 g, after assay adjustment, 131.14 mmol, 1.00 eq., 98.4% e.e.) inMeOH (53.0 mL, 1.31 mol, 10.00 eq.) and THF (500 mL) was added NaBH₄(1.84 g, 48.64 mmol, 0.37 eq.) in portions at −5 to 0° C. The reactionmixture was stirred at −5 to 0° C. for an additional hour, then quenchedwith 2.0 M aqueous HCl (about 30.0 g) below 5° C. to pH=5-7 and dilutedwith water. The mixture was extracted with MTBE, and the combinedorganic layer was washed with water and 10% brine. The organic layer wasconcentrated, and the solvent was exchanged to THF to obtain a THFsolution of the title compound (286.66 g, 16.6% assay purity, 94.7%assay yield, 97.7% e.e.). ¹H NMR (400 MHz, CDCl₃) δ=7.55 (d, 1H),7.18-7.16 (m, 2H), 7.13 (d, 1H), 7.08 (d, 1H), 5.89-5.84 (m, 1H), 3.06(s, 1H), 2.83-2.78 (m, 1H), 2.47-2.42 (m, 1H), 2.35 (d, 1H).

What is claimed:
 1. A process of preparing compound (11):

comprising reducing the keto moiety of compound (10):

with a suitable reducing agent in a suitable organic solvent andoptionally in the presence of an organic acid.
 2. The process of claim1, wherein the reducing agent is sodium borohydride, lithiumborohydride, sodium acetoxy borohydride, or sodium cyanoborohydride. 3.The process of claim 1, wherein the reduction of the keto group ofcompound (10) is carried out with sodium borohydride in tetrahydrofuran,2-methyltetrahydrofuran, a mixture of tetrahydrofuran or2-methyltetrahydrofuran and methanol, tetrahydrofuran containing aceticacid or trifluoroacetic acid, 2-methyltetrahydrofuran containing aceticacid or trifluoroacetic acid, or methanol containing acetic acid ortrifluoroacetic acid.
 4. The process of claim 3, wherein the organicsolvent is a mixture of tetrahydrofuran and methanol and the reaction iscarried out at about −5° C. to about 30° C.
 5. A process of preparingcompound (10):

comprising reacting compound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent.
 6. The process of claim 1, further comprisingpreparing compound (10):

by reacting compound (9):

with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in asuitable organic solvent.
 7. The process of claim 5, wherein the base isan inorganic base.
 8. The process of claim 6, wherein the base is aninorganic base.
 9. The process of claim 6, wherein the base is cesiumcarbonate or potassium carbonate, and the organic solvent istetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide,acetonitrile, or toluene.
 10. The process of claim 9, further comprisingcrystallizing compound (10) from a mixture of an ether and an alkanesolvent.
 11. The process of claim 10, wherein compound (10) iscrystallized from a mixture of methyl tert-butyl ether and n-heptane.12. A process for preparing compound (9):

comprising carrying out oxidative cleavage of the vinylidene moiety ofcompound (8).

with a suitable oxidizing agent in a suitable organic or aqueous organicsolvent.
 13. The process of claim 12, wherein the oxidative cleavage ofthe vinylidene moiety of compound (8) is carried out with (i) sodiumperiodate in the presence of ruthenium chloride in aqueous acetonitrile,(ii) Oxone in the presence of ruthenium chloride in a suitable organicor aqueous organic solvent, or (iii) Ozone in a suitable organic oraqueous organic solvent.
 14. The process of claim 5, further comprisingpreparing compound (9):

by carrying out oxidative cleavage of the vinylidene moiety of compound(8):

with a suitable oxidizing agent in a suitable organic or aqueous organicsolvent.
 15. The process of claim 9, further comprising preparingcompound (9):

by carrying out oxidative cleavage of the vinylidene moiety of compound(8):

with a suitable oxidizing agent in a suitable organic or aqueous organicsolvent.
 16. The process of claim 15, wherein the oxidative cleavage ofthe vinylidene is carried out with (i) sodium periodate or Oxone in thepresence of ruthenium chloride or (ii) Ozone.
 17. The process of claim15, wherein the oxidative cleavage of the vinylidene is carried out withsodium periodate in the presence of catalytic amount of rutheniumchloride in aqueous acetonitrile.
 18. A process for preparing compound(8):

comprising performing intramolecular cyclization between the alkene andbromo groups in compound (7):

by treating compound (7) with a palladium catalyst in the presence of abase in a suitable organic or aqueous organic solvent.
 19. The processof claim 18, wherein the palladium catalyst is Pd(PPh₃)₄, Pd(dppf)Cl₂,Pd(PPh₃)₂Cl₂, Pd(PPh₃)₂(OAc)₂, Pd₂(dba)₃/XPhos, orPd(1,2-bis(diphenylphosphino)-ethane)(OAc)₂, and the organic solvent isacetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene,1,4-dioxane, or dimethylformamide.
 20. The process of claim 16, furthercomprising preparing compound (8):

by performing intramolecular cyclization between the alkene and bromogroups in compound (7):

with a palladium catalyst in the presence of a base in a suitableorganic solvent.
 21. The process of claim 20, wherein the palladiumcatalyst is Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd(PPh₃)₂(OAc)₂,Pd₂(dba)₃/XPhos, or Pd(1,2-bis(diphenylphosphino)-ethane)(OAc)₂, and theorganic solvent is acetonitrile, tetrahydrofuran,2-methyltetrahydrofuran, toluene, 1,4-dioxane, or dimethylformamide. 22.The process of claim 21, wherein the base is sodium acetate, potassiumacetate, sodium carbonate, potassium carbonate, or cesium carbonate. 23.The process of claim 20, wherein the palladium catalyst is Pd(PPh₃)₂Cl₂,the base is potassium acetate, and the solvent is acetonitrile.
 24. Aprocess for preparing compound (7):

comprising brominating compound (6):

with a brominating agent in the presence of a deprotonating agent in asuitable organic solvent.
 25. The process of claim 24, wherein compound(6) is brominated with 1,2-dibromo-1,1,2,2-tetrafluoroethane in thepresence of a deprotonating agent in a suitable organic solvent.
 26. Theprocess of claim 21, further comprising preparing compound (7):

by treating compound (6):

with a brominating agent in the presence of a deprotonating agent in asuitable organic solvent.
 27. The process of claim 26, wherein thebrominating agent is carbon tetrabromide or1,2-dibromo-1,1,2,2-tetrafluoroethane.
 28. The process of claim 26wherein the brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane,the deprotonating agent is lithium diisopropylamide, and the solvent istetrahydrofuran.
 29. The process of claim 26, further comprisingpreparing compound (6):

by treating compound (5):

with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane in thepresence of(S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamideand a base in a suitable organic solvent.
 30. The process of claim 29,wherein the base is sodium tert-butoxide and the organic solvent is amixture of methanol and toluene.
 31. The process of claim 29, furthercomprising preparing compound (5):

by treating compound (4):

with an organolithium reagent in a suitable organic solvent.
 32. Theprocess of claim 31, wherein the organolithium reagent is n-butyllithiumand the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran,n-heptane, and methyl tert-butylether.
 33. The process of claim 31,further comprising preparing compound (4):

by treating compound (3):

with a fluorinating agent in a suitable organic solvent.
 34. The processof claim 32, wherein the fluorinating agent is diethylaminosulfurtrifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, orsulfur tetrafluoride and hydrofluoric acid.
 35. The process of claim 33,further comprising preparing compound (3):

by treating compound (2):

with an oxidizing agent in a suitable organic solvent.
 36. The processof claim 35, wherein the oxidizing agent is dimethyl sulfoxide/oxalylchloride, 2-iodoxybenzoic acid, RuCl₃/NaBrO₃, MnO₂, NaBrO₃/NaHSO₃, orTPAP/NMO.
 37. The process of claim 35, further comprising preparingcompound (2):

by treating compound (1):

with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal,trimethylsilyl chloride, and 1,2-dibromoethane in a suitable organicsolvent.